This application is a 371 of PCT/EP00/02323 filed Mar. 16, 2000.
The invention relates to a process for the production of 4,4-dimethyl-3xcex2-hydroxy-pregna-8,14-diene-21-carboxylic acid esters (1) and intermediate products in the process 
in which R1=hydrogen, branched or unbranched C1-C6 alkyl, phenyl, benzyl, ortho-, meta- or para-methylphenyl, and the use for the production of 4,4-dimethyl-5xcex1-cholesta-8,14,24-trien-3xcex2-ol (2) (FF-MAS) 
Studies by Byskov et al. (Nature 1995, 374, 559) show that 4,4-dimethyl-5xcex1-cholesta-8,14,24-trien-3xcex2-ol, formula 2, mentioned in the FF-MAS below and isolated from human follicular fluid, is an endogenous substance that regulates meiosis, to which advantageous hormonal effects are ascribed. This substance is thus important for pharmaceutical applications, for example for promoting fertility.
A first synthesis of this natural substance, which will take place in the biosynthesis of cholesterol from lanosterol, was described by Dolle et al. (J. Am. Chem. Soc. 1989, 111, 278). Starting from ergosterol, FF-MAS is obtained in an 18-stage resource-intensive synthesis sequence. Large portions of the synthesis are devoted to the chemical partial degradation of the ergosterol side chain, the subsequent creation of the FF-MAS side chain and the protective group chemistry that is necessary for achieving this goal.
A second synthesis of FF-MAS was described by Schroepfer et al., starting from dehydrocholesterol in a 13-stage synthesis (Bioorg. Med. Chem. Lett. 1997, 8, 233). Also in this synthesis, an resource-intensive protection of the diene system must be performed for the creation of a side-chain. Only four steps (epoxidation and rearrangement for protection; reduction and elimination for regeneration of the diene system) are due to the protective group strategy.
A third synthesis of FF-MAS was developed by Ruan et al. (Med. Chem. Letters 1998, 233). In this case, FF-MAS is built up starting from cholesterol in a 15-stage synthesis. Here, large portions of the synthesis are devoted to the resource-intensive build-up of the double-bond system in the steroid and the creation of the side-chain.
Additional processes are described within the still unpublished DE 198 17 520 and 198 23 677. These syntheses start from 3-oxopregn-4-ene-21-carboxylic acid esters. Central intermediate products of these processes are the 4,4-dimethyl-3xcex2-hydroxypregna-8,14-diene-21-carboxylic acid esters that are described under general formula 1.
The object of this invention are new processes for the synthesis of these central intermediate stages. Also subjects of this invention are the new, previously unknown intermediate products that will be within the context of syntheses and can be used per se or derivatized as starting materials for the synthesis of other target molecules, for example for the synthesis of FF-MAS analogs (see WO 96/00235) and the use of compounds for the production of 4,4-dimethyl-5xcex1-cholesta-8,14,24-trien-3xcex2-ol.
This object is achieved by the teaching of the claims.
By the process according to the invention, there will be fewer intermediate stages than in the known syntheses from the prior art, and the number of purification steps is considerably lower.
According to Diagram 1,4,4-dimethyl-3xcex2-hydroxypregna-8,14-diene-21-carboxylic acid esters of general formula 1 are produced in a 5-stage sequence starting from androstenedione (3).
The androstenedione that is used as starting material is commercially available.

The reaction of a compound of formula 3 to form a compound of formula 4 is carried out according to processes that are known in the art (e.g., Helv. Chim. Acta 1980, 63, 1554; J. Am. Chem. Soc. 1954, 76, 2852). For example, a compound of formula 3 is reacted in the presence of bases, such as, for example, the alkali salts of lower alcohols, but preferably potassium tert-butylate with an alkylating agent, such as, for example, dimethyl sulfate, dimethyl carbonate or else methyl iodide in a solvent or solvent mixture. As solvents, lower alcohols, preferably tertiary alcohols as well as ethers, for example methyl tert-butyl ether, or tetrahydrofuran and mixtures thereof can be used. Preferred is the use of tert-butanol or a mixture that consists of tert-butanol and tetrahydrofuran. The reaction is performed in a temperature range of 0xc2x0 C. to 65xc2x0 C., but preferably in a temperature range of 15xc2x0 C. to 50xc2x0 C.
The reaction of a compound of formula 4 to form a compound of formula 5 is carried out according to processes that are known in the art (e.g., Synth. Commun. 1977, 7, 215; JOC 1988, 3947; J. Prakt. Chem. 1990, 367). For example, a compound of formula 4 is reacted in the presence of bases, such as, for example, the alkali salts of lower alcohols, but preferably sodium methylate, with a trialkylphosphonoacetate, such as, for example, triethylphosphonoacetate or trimethylphosphonoacetate in a solvent or solvent mixture. As solvents, lower, preferably primary alcohols, as well as ethers, for example methyl tert-butyl ether, or tetrahydrofuran and mixtures thereof, can be used. Preferred is the use of ethanol. The reaction is performed in a temperature range of 0xc2x0 C. to 100xc2x0 C., but preferably in a temperature range of 20xc2x0 C. to 80xc2x0 C.
Starting from a compound of formula 4, a compound of formula 5 can also be produced via condensation with Meldrum""s acid or malonic acid esters, then saponification and decarboxylation and esterification.
It is familiar to one skilled in the art that R1 can be varied in compounds of formula 5 according to standard methods. This can happen by using other alcohols in the esterification step, but also by reesterification of an already present ester. R1 can thus have the meaning of hydrogen, methyl, ethyl, propyl, isopropyl, butyl, and the corresponding butyl isomers, pentyl and the corresponding pentyl isomers as well as hexyl and the corresponding hexyl isomers, phenyl, benzyl, ortho-, meta- and para-methylphenyl.
The reaction of a ketone of formula 5 in the corresponding 3-alcohol of formula 6 can be performed with a considerable number of reducing agents. As examples, there can be mentioned: BH3 complexes (e.g., with tert-butylamine or trimethylamine), selectrides, sodium and lithium borohydride, inhibited lithium aluminum hydrides (e.g., LiAl(OtBu)3H); microorganisms such as, e.g., baker""s yeasts or enzymes, for example 3xcex2-hydroxysteroid dehydrogenase, can also be used.
It is known to one skilled in the art that depending on the reagent that is used, various solvents or solvent mixtures and reaction temperatures are used. Preferred here, however, are borohydrides, such as, for example, sodium borohydride, in suitable solvents, such as, for example, lower alcohols or mixtures of alcohols with other solvents, for example dichloromethane, tetrahydrofuran or water. The reactions are performed in a temperature range of xe2x88x9220xc2x0 C. to 40xc2x0 C., but preferably in the range of xe2x88x9210xc2x0 C. to 10xc2x0 C.
The reduction of the 17-double bond in the compounds of general formula 6 is possible according to processes that are known in the art. In this case, two fundamentally different processes can be used.
In this connection, in a way that is similar to reactions that are known in the literature (Synthesis 1996, 455), a suitable reducing agent is a mixture of alkaline-earth metals in lower alcohols. For example, a compound of general formula 6 is reacted in a lower alcohol, preferably methanol, with an alkaline-earth metal, preferably magnesium. The reaction is performed in a temperature range of 0xc2x0 C. to 80xc2x0 C., but preferably in a temperature range of 20xc2x0 C. to 50xc2x0 C.
As a further reduction process, in this case the catalytic hydrogenation is presented. For example, a compound of formula 6 is hydrogenated in the presence of a suitable catalyst, such as, for example, noble metals or oxides thereof, but preferably platinum oxide. As solvents, lower alcohols, preferably ethanol, as well as ethers, for example methyl tert-butyl ether, or tetrahydrofuran or mixtures thereof, can be used. Preferred is the use of tetrahydrofuran. In this case, surprisingly enough, the 5,6-double bond is not hydrogenated.
The addition of catalytic amounts of acid, such as, for example, sulfuric acid, phosphoric acid or citric acid, has proven advantageous. Preferred is the use of phosphoric acid. The reaction is performed in a temperature range of 10xc2x0 C. to 100xc2x0 C.; it can be performed both under normal pressure and under increased pressure. Preferred in this connection is the reaction in the temperature range of 20xc2x0 C. to 50xc2x0 C. and under normal pressure.
The introduction of the 7,8-double bond and the isomerization of the double bonds to the double-bond system that is established in the target compound can be achieved in a single-pot process by bromination/dhydrobromination/isomerization (this is also the method using the corresponding chloride and dehydrochlorination).
First, bromination is done with allyl to form the 5,6-double bond in 7-position, and then by thermal elimination of hydrogen bromide, the 5,7-double bond system is obtained, which turns into the desired double-bond system by acidic isomerization. The addition of acid is not necessary; the hydrogen bromide that is formed in the meantime takes over this object in a satisfactory manner.
The bromination is done according to processes that are known in the art. For example, N-bromosuccinimide or N,N-dibromodimethylhydantoin can be used in a suitable solvent, such as, for example, benzene, lower alkanes or else halogenated hydrocarbons, such as, for example, carbon tetrachloride. Solvents other than those previously mentioned, for example methyl formate, can also be used, however (e.g., Angew. Chem. [Applied Chemistry] 1980, 92, 471).
Preferred is the use of heptane as a solvent. The reaction is performed in a temperature range of 30xc2x0 C. to 130xc2x0 C., but preferably in a temperature range of 60xc2x0 C. to 100xc2x0 C.